Considerable evidence exists linking the renal parenchyma to the degradation of a variety of polypeptides, some of which have important hormonal activities. Since uremic individuals have elevated levels of many hormones, or respond inappropriately to both stimulatory and suppressive maneuvers, it has been proposed that the reduction in functioning kidney mass associated with renal failure accounts for these abnormalities. However experimental proof for this hypothesis is incomplete and the role of uremia per se in the pathogenesis of endocrine disorders has not been adequately evaluated. The proposed investigation will address itself to these questions and attempt to clarify the contribution of the kidney to the metabolism of glucagon, TSH and prolactin. In addition, the role of the uremic state per se in the pathogenesis of the hormonal abnormalities associated with renal failure will be evaluated. Baseline, poststimulation, and postsuppression hormonal levels and metabolic clearance rates will be measured by radioimmunoassay in control rats and animals rendered uremic by either renal ablative maneuvers (bilateral nephrectomy or ureteral ligation) or by a urine reinfusion technique whereby uremia can be maintained for up to a week while the kidneys remain normal in structure and function. Comparison of the effect of ureteral ligation and nephrectomy on hormonal levels will provide information about the inactivation of these peptides by the renal parenchyma. Evaluation of the hormonal responses of uremic animals with intact kidneys will shed light on the role of uremia per se in causing abnormalities of hormonal metabolism in renal insufficiency. Finally, the homogeneity of the immunoreactive hormones will be evaluated by column fractionation. The data to be obtained will help clarify the pathophysiology of certain endocrine abnormalities in renal failure, and provide theoretical information on the nature of the circulating hormones in uremia and on the role of the renal parenchyma in the degradation of hormonally active peptides.